Aralkyl morpholines



Patented Sept. 3, 1940 anon-a ARALKYL MOBPHOLINES Marlin T. Leffler,Lake Bluff, 111., assignor to Abbott Laboratories, North Ghicago, 111.,a corporation of Illinois No Drawing. Application September 20, 1937,Serial No. 164,759

8 Claims.

The present invention relates to aralkyl morpholines and more inparticular to halogenated and amino substituted aralkyl morpholines.

The compounds of my invention may be represented by the followinggeneral formula:

in which R represents a substituted or unsubstituted phenyl or naphthylgroup, A represents a saturated or unsaturated aliphatic hydrocarbongroup and X and Y represent hydrogen or alkyl groups.

More particularly the present invention relates to the use as localanesthetics of morpholine compounds represented by the followingformula:

in which R represents a phenyl group including substituted phenyl groupin which the substituent is a halogen atom, amino group or an alkoxygroup, R. represents hydrogen or a methyl group, and X and Y representhydrogen or alkyl groups.

I have discovered that the compounds of my invention possess pronouncedand valuable local anesthetic properties. For example, investigationshave shown the compounds to possess a low toxicity coupled with a highefficiency.

The following examples describing the preparation of various compoundsof my invention will serve for illustrative purposes:

EXAMPLE I (N) P-a.minobenzyl morpholine About 35 grams of morpholine andabout 34.3 grams of p-nitrobenzyl chloride are dissolved in about 150 c.c. of dry benzene. The solution is then heated at a refluxingtemperature for about 5 to 6 hours during which time some morpholinehydrochloride separates. At the completion of the reaction, the reactionmixture is cooled and the solid material is separated from the liquid byfiltration. The clear filtrate is then extracted twice with waterand thebenzene layer dried over anhydrous sodium sulfate. Upon evaporation ofthe benzene the crude p-nitro-benzyl morpholine is obtained. Thisproduct may be purified in the usual manner by recrystallization 10 fromalcohol. The final product which is in the form of'light yellow prismshas a melting point of about 79-80 C.

The nitrobenzyl morpholine may be reduced I p to the aminobenzylmorpholine by the usual pro- 15 cedure, e. g. by the use of an excess ofiron turnings in practically a neutral solution, a few drops ofconcentrated hydrochloric acid being added to start the reaction. Assoon as the reduction is complete most of the water is allowed to evap-3, crate and the p-aminobenzyl morpholine extracted from the mixturewith hot benzene. Subsequent vacuum evaporation of the solvent andrecrystallization of the residue from ethyl acetate gives p-aminobenzylmorpholine as color- 25 less leaflets melting at about 100.5-l01.5 C.

The. p-aminobenzyl morpholine monohydrochloride may be prepared byadding the calculated amount of absolute alcoholic hydrogen chloride toa solution of the free base dissolved 3G in a mixture of ethyl acetateand pentane. The hydrochloride separates as a pale yellow solid whichmay be recrystallized from a'mixture of ethyl acetate and absolutealcohol in leaflet form.

The p-aminobenzyl morpholine hydrochloride 5' melts at about l88-l90 C.

In a manner similar to that described in EX- ample 1, other aminoderivatives together with the bromo-, chloro-, and alkoxy-derivativesmay be prepared by condensing morpholine with the 40 properlysubstituted aralkyl halide. Similarly to the method described in ExampleI, the phenylethyl-, phenyl-propyl-, etc., together with thenaphthyl-alkyl-morpholines may be prepared by selecting the properaralkyl derivative. By iol- 45 lowing the method described in Example Iit is likewise possible to prepare derivatives in which the alkyl groupconnecting the aromatic hydrocarbon group to the morpholine group isunsaturated. For example, a derivative containing an unsaturated alkylgroup may be prepared by condensing cinnamyl halide with morpholine.

In addition, my invention includes derivatives in which the morpholinegroup contains alkyl groups such as methyl, ethyl, propyl, etc.,substituted on the 2, 3, 5 and 6 positions. These derivatives may beprepared by the method described in Example I by condensing the aralkylhalide with the properly alkyl substituted morpholine.

The following example will illustrate the preparation of the halogen,amino-substituted aralkyl morpholine derivatives.

EXAMPLE II (N) -m,m-dibromo-p-aminobenzyl morpholine A solution of about16 grams of bromine dissolved in about 35 0.0. of glacial acetic acid isadded dropwise with stirring to a solution of about 9.6 grams ofp-amino-benzyl morpholine (prepared as in Example I) dissolved in about0.0. of glacial acetic acid. The temperature of the reaction mixtureshould be maintained at about 15-20 C. during the addition of thebromine. As soon as all of the bromine has been added, the solidmaterial is separated by filtration and dissolved in water. The coldfiltered solution is then made alkaline with dilute sodium period. Whenthe reaction is complete the cooled mixture is washed rapidly with coldwater and dried over anhydrous sodium sulphate. The solvent is thenremoved and the residue vacuum distilled in the usual manner. The4-butoxy-3- nitrobenzyl chloride distills at 162-165 C. at 3-4 mm.pressure.

The alkoxy-nitrobenzyl chloride may be converted by reaction withmorpholine to alkoxybenzyl-morpholine and by reduction with ironturnings to the alkoxy-aminobenzyl-morpholine compound by a processsimilar to that described under Example I. The reaction may beillustrated by the following formula:

CHE-CH2 NO omjpfij-j-jijN o CHz-CH: (3 119.0

- Reduction with Fe CHPGHQ NH CH2N O CHg-Oi C4H9.0

The following table listing the properties of the base andhydroohlorides will serve to illustrate various compounds of myinvention:

Table Melting Product Boiling point (B. P.) or melting point ofCrystalline form of point (M. P.) of base hydrohydrochloride chloride (N)-Benzyi morpholine B. p. 108110 C. at 4 mm. 246-247 Colorless plates.(N )-Phenethyl-morpholine B. p. 107108 C. at 238 Spur needles.

(N a) -phenylethyl morpholine 2112l2 Colorless needles. (N)-'v-phenylpropyl-morpholine B. p. l131l5 C. at 2 mm. 138-139 Fluffyneedles. (N )-Cinnamyl-morpholine. B. p 132-134" C at 3 mm 216 Colorlessneedles. (N )-pAminobenzyl-Inorpholin M. p. 100.5-10 188-l90 Yellowleaflets. (N)-ominobenzyl-morpholin B. p. 150 C. at 4 mm(N)-p-Aminophenethyl-morpholine. M. 80.58l.5 Yellow fiekes.(N)-('y)-p-Aminophenyl-propyl-morpholine. B. p. l60 C. at 2 mm l97-198Colorless plates. (N)-Benzy1-2,G-dimethyl-morpholine B. p. 102-104 C. at3 mm. 184-185 Needles. (N)-'yphenylpropyl-2,e-dimethyl-morpholine B. p.1l5ll8 C. at 3 mm. (N)-Ci.nnamyl-2,G-dimethyl-morpholme.. B. p. 140-142C. at 2-3 mm. (N)-p-Aminobenzyl-2,6-dimethyl-rnorphol1ne Needles.

(N) -p-Bromobenzy1-morpholine Colorless prisms.

N )-0-Bromobenzyl-morpholine Colorless needles. (N)-p-Chlorobenzyl-morpholine Colorless plates.(N)-p-Chlorobenzyl-2,fi-dimethyl-morphohne Colorless needles. (N)-m,n1-dibromo-p-an1inobenzyl-morpholme- Colorless prism.

N )-p-Amino-m-bromo-benzyl-morpholine. (N) -o-(n)-Butoxybenzyl-morpholine N eedlelike prisms.(1:11)igmethoxy-m-aminobenzyl-morpholine-dihy- Needles.

(N) -p-(n) -Butoxy-m-aminobenzyl-morpholine Needles.

(N) -p-Butoxy-m-hromob enzyl-morphohne PllSlIlS. (N) -p-(n)-Butylaminobenzyl-morpholine. o. (N)-(a)-Naphthyl-methyl morpholineColorless needles.

hydroxide and the m,m'-dibromo-p-aminobenzyl morpholine separates as anoil which soon solidifies. The final product recrystallized from alcoholmelts at about 61-62 C.

The following example will illustrate the preparation of thealkoxy-substituted aralkyl morpholine compounds.

EXAMPLE III 4-butomy-3-aminobenayl morpholine A mixture of about 78.4grams of o-butoxynitro-benzene, 9 grams of para-formaldehyde, 1 gram ofanhydrous zinc chloride and 300 0.0 of petroleum ether (b. pt. 85100 C.)is treated for about 5 hours under eflicient stirring with a vigorousstream of dry hydrogen chloride. At the end of this time the temperatureof the reaction mixture is raised to about 85 C. where it is held for 10hours, the stirring and hydrogen chloride treatment being continuedthroughout the entire Or" the compounds coming within my invention,investigations have shown the halogen and particularly the brominesubstituted aralkyl morpholines to possess properties making themparticularly adaptable for use as local anesthetics. Investigations havealso shown the amino substituted aralkyl morpholines to possess unusualproperties which make them particularly adaptable for use as localanesthetics.

It will be obvious to those skilled in the art that my invention is notlimited to the above described examples. It will also be obvious tothose skilled in the art that the compounds of my invention may be usedin the form of the base or in the form of salts, i. e. hydrochloride,and that the claims appended hereto directed to the base are intended toinclude the usual salt forms. All modifications coming within the truespirit and scope of my invention are intended to be covered by theclaims annexed hereto.

I claim:

1. A bromo-benzyl morpholine.

2. (N) -p-bromobenzyl-morpholine.

3. An amino-benzyl mcrpholine.

4. (N) -p-aminobenzy1-morpho1ine.

5. (N) -m,m'-dibro-mo-p-aminobenzy1-morpholine.

6. A product having the formula:

X Y X Y in which It represents a halogen substituted phenyl group, R isselected from the group consisting of hydrogen and methyl groups and Xand Y are selected from the group consisting of 0 hydrogen and alkylgroups.

7. A product having the formula:

X\ /Y X\ /Y RCHRN\ O c X in which R represents an amino substitutedphenyi'group, R is selected from the group consisting of hydrogen andmethyl groups, and X and Y are selected. from the group cohsistingofhydrogen and alkyl groups.

8. A compound having the following formula:

in which R is selected from the groupconsisting of halogen, amino andalkoxy substituted phenyl groups, R is selected from the groupconsisting of hydrogen and. methyl groups and X and Y are selected from.the group consisting of hydrogen and alkyl groups.

MARLIN T. LEFFLER. 2s

